This study is designed to develop a fundamental understanding of the mechanisms by which retroviruses induce immunodeficiency. The central focus is on mice infected with the LP-BM5 mixture of murine leukemia viruses (MuLV) which causes progressive lymphoproliferation and severe immunodeficiency, a syndrome termed mouse AIDS (MAIDS) in some inbred strains. This virus mixture includes an etiologic replication defective virus (BM5def) that encodes a unique gag polyprotein only and can induce disease given on its own. Our efforts have been directed at: a) determining the cell types targeted for infection by BM5def; b) examining the consequences of infection with this virus in terms of cytokine expression and evaluating the contributions of cytokines to disease resistance or sensitivity; c) examining the possible therapeutic potentials of IL-12 treatment of infected mice and possible prevention of MAIDS by vaccination of mice with vaccinia recombinants carrying the BM5def gag gene. Our analyses showed that B cells are the immediate target for infection and the efficient infection of T cells and macrophages requires the presence of B cells. A crucial role for MHC class II antigens in MAIDS was revealed by the finding that no disease develops in mice incapable of expressing class II molecules. The pattern of cytokine expression in infected susceptible mice includes high level transcription of interferon gamma, IL-4 and IL-10. Use of mice deficient in expression of these cytokines demonstrated that IL-4 and IL-10 are not required for induction of MAIDS and that more disease develops in interferon gamma knockouts. Importantly, it was found that mice treated with IL-12, a cytokine that stimulates Th1 cells and interferon gamma expression, had a markedly beneficial effect on the course of MAIDS. Future studies will be directed at understanding how immunization or IL- 12 treatment exert their positive effects on MAIDS.